General expression patterns
Costimulatory molecules appear on the cell membrane following cell activation: either the proteins are synthesized de novo, or the cell sharply upregulates their initially weak basal expression.
Features of the costimulatory system:
- Cascading: the successful interaction of one pair of molecules often serves as a signal for the appearance of another.
- Redundancy: ligands are often represented by multiple molecules with similar functions, so the loss of one of them does not always result in a clinical presentation.
- Dual control: the surface of the same cell can simultaneously carry receptors receiving opposing signals (activating and suppressive).
Main families and signaling pathways
Most costimulatory molecules belong to the immunoglobulin superfamily or the tumor necrosis factor (TNF) family. They can be divided into two functional groups.
Activating pathways (stimulation of the response):
- CD28 (Ig superfamily, mass 44 kDa). Located on T cells. Binds to ligands CD80 (B7-1) and CD86 (B7-2) expressed by antigen-presenting cells (APCs). Transmits a signal via the YXXM / MYPPPY motif, inducing IL-2 secretion.
- ICOS. Located on activated T lymphocytes (Th2 predominate over Th1) and NK cells. Binds ICOSL on APCs. Stimulates cytokine production.
- CD154 (CD40L). Belongs to the TNF family (34–39 kDa). Located on activated T cells, binds to the CD40 receptor on APCs.
Suppressive pathways (inhibition of the response):
- CTLA-4 (CD152). Appears on activated T cells. Competes with CD28 for the same ligands (CD80 and CD86) but has an extremely high affinity for them and suppresses cell activity.
- PD-1. Expressed by activated T and B cells, and macrophages. Binds to PD-L1 and PD-L2. Contains an intracellular inhibitory motif ITIM, suppressing T cell development.
- BTLA. Located on T cells (Th1 predominate over Th2) and B lymphocytes. Binds B7-H4, suppressing activation via the 2 ITIM motif.
CD28 — CD80/CD86 system
This is the most studied pair, ensuring T cell viability and IL-2 production. The CD28 receptor is a homodimer spontaneously expressed on 80% of T cells. Inside the cell, it contains a binding site for the PI3K kinase.
Its ligands — CD80 and CD86 — are initially almost absent on resting APCs. The signal for their translocation to the membrane is contact between the CD40–CD154 pairs.
The dynamics of ligand appearance differ:
- CD86 is responsible for the early stages of costimulation, with its expression peaking after 2 days.
- CD80 is upregulated later, reaching its maximum by days 4–5.
Due to the signal from CD28, the T cell requires fewer contacts between its receptor (TCR) and the MHC-peptide complex, and the required intercellular interaction time is shortened. In the absence of costimulation, the T lymphocyte enters a state of cellular anergy — it loses the ability to respond to subsequent stimuli.
CTLA-4 system and termination of the immune response
CTLA-4 (Cytotoxic T lymphocyte activation molecule 1) is 30% homologous to the CD28 molecule, but acts as a "brake". It begins to be expressed shortly after the initiation of costimulation, although for the first 48–72 hours it accumulates inside the cell.
When CTLA-4 reaches the membrane in the immunological synapse area, it intercepts CD80/86 ligands from CD28 due to its enormous affinity. This event marks the final point of activation, after which the immunological synapse ceases to function.
CD40 and CD40L (CD154) interaction
The CD40 receptor (TNF family) is constitutively present on APCs. It lacks a typical "death domain". Its ligand CD154, a type II transmembrane protein, appears on T cells on days 3–4 of the response.
The main feature of this pair is that upon contact, CD40 trimerization occurs, and the activating signal is directed toward the APC rather than the T cell. This leads to potent activation of macrophages, dendritic cells, and B lymphocytes. Disruptions in these genes lead to severe consequences: CD40 knockout disrupts cellular immunity (defect in Th1 and IFNγ production), while a CD40L mutation causes a primary immunodeficiency — hyper-IgM syndrome.
Briefly: answers to topical questions
What intracellular signaling pathways are triggered by the CD28 receptor?
The CD28 receptor triggers several intracellular signaling cascades, the key one being the activation of the lipid kinase PI3K.
- PI3K/Vav/PKCθ pathway (PI3K/Vav/PKCθ) — PI3K catalyzes the formation of phosphatidylinositol-4,5-bisphosphate, which activates the Vav factor, which recruits the PKCθ protein kinase. This leads to the formation of the NF-κB and AP-1 transcription factors, as well as the activation of the Rac/JNK branch of the MAP kinase cascade.
- Lck/Fyn cascade (Lck/Fyn) — signal transduction proceeds via the Lck/Fyn → PKB/Akt → mTor pathway, providing costimulation.
These pathways ensure the maintenance of T cell viability, enhanced adhesion, and cytokine production (especially IL-2).
Through what mechanisms does the CTLA-4 molecule suppress the immune response?
The CTLA-4 molecule suppresses the immune response through competitive ligand binding and activation of intracellular phosphatases.
- Competition for ligands (CD80/CD86) — the affinity of CTLA-4 for CD80 and CD86 molecules is 1000–2500 times higher than that of the activating receptor CD28.
- Intracellular signaling (SHP2/PP2A) — the cytoplasmic domain (especially tyrosine residue 165) interacts with SHP2 and PP2A phosphatases.
- Blockade of costimulation (PKB/Akt) — the PP2A phosphatase blocks the PKB/Akt pathway by dephosphorylating signaling proteins.
- Attenuation of activation (Cbl-b/Rap) — activation of Cbl-b and Rap molecules directly inhibits the T cell.
Ultimately, CTLA-4 promotes the "dismantling" of the immunological synapse.
Which costimulatory molecules belong to the tumor necrosis factor (TNF) family?
A number of costimulatory molecules involved in intercellular interactions belong to the tumor necrosis factor (TNF) superfamily and its receptors (TNFR).
- CD40 (CD40) — a receptor on antigen-presenting cells lacking a death domain.
- CD154 (CD40L) — a ligand on activated T cells, a B cell costimulator.
- GITR (Glucocorticoid-induced TNFR-related) — a surface molecule characteristic of regulatory T cells.
- OX40-L (OX40L) — a costimulatory molecule on dendritic cells (ligand for the OX40 receptor).
Membrane molecules of the TNF superfamily also include FasL, BAFF, TRAIL, APRIL, and LIGHT.
Which costimulatory molecules are characteristic of regulatory T cells (Treg)?
Regulatory T cells (Treg) are characterized by the expression of suppressive analogs of costimulatory molecules and members of the TNFR family.
- CTLA-4 (CD152) — a suppressive analog of CD28, critical for contact-dependent inhibition of autospecific clones.
- PD-1 (Programmed death-1) — an inhibitory receptor involved in suppressing T cell activity.
- GITR (Glucocorticoid-induced TNFR-related) — a receptor from the tumor necrosis factor family.
These surface molecules are part of the classical membrane phenotype of human Treg cells, along with the CD4 and CD25 markers.
To remember the expression timing of APC ligands: CD86 — the number is higher, but it acts earlier (peak on day 2). CD80 — the number is lower, but it turns on later (on days 4–5).
Class and exam questions
What is cellular anergy?
This is a state where a T lymphocyte loses its ability to respond to signals from the antigen-recognition receptor (TCR). It occurs if the cell has recognized an antigen but has not received a confirmatory co-stimulatory signal.
Why does the signal from CTLA-4 override the signal from CD28?
The CTLA-4 molecule has an affinity for the same ligands (CD80 and CD86) as CD28, but it is 1000–2500 times higher. By moving to the membrane, CTLA-4 competitively displaces the activating receptor and suppresses the immune synapse.
How does NK cell activation differ from that of T lymphocytes?
T-cell activation strictly requires exiting the resting state and triggering proliferation (clonal expansion). NK cells lack a clonal structure, so their activation is not associated with proliferation, but merely shifts the cell into a ready-to-kill state.
What else to study on this topic
- Molecular basis of T lymphocyte cell cycle initiation
- Role of IL-2 and its receptor alpha chain in clonal expansion
- Cell adhesion molecules: LFA-1 and VLA-4 integrins
- Mechanisms of hyper-IgM syndrome development
- Transcription factors and regulation of inducible genes
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